Amiodarone-Induced Myxedema Coma in Elderly Patients: A Systematic Review of Case Reports

This systematic review aimed to explore whether elderly patients administered amiodarone were susceptible to developing myxedema coma. Utilizing the Cochrane guidelines, a comprehensive review of databases such as Medline (PubMed), Science Direct, CINAHL Cochrane, and Google Scholar was undertaken to examine case reports on amiodarone-induced myxedema coma. Following stringent criteria for inclusion, 12 pertinent case reports were identified. These findings suggested a high probability of myxedema coma development in patients who had been administered amiodarone. Specifically, patients who received an oral dosage of 100-200 mg of amiodarone were reported to have developed bradycardia and hypothermia alongside elevated thyroid-stimulating hormone (TSH) levels. Upon diagnosis, the majority of patients were treated with a regimen of levothyroxine and hydrocortisone medication. Despite the myriad potential causes of myxedema coma complicating the diagnosis, it was found that through a combination of clinical symptoms and serum TSH measurements, a confirmed diagnosis could be reached. Furthermore, it was observed that amiodarone-induced myxedema coma responded favorably to treatment with levothyroxine and glucocorticoids.

However, its frequent usage could disrupt thyroid function and other organ systems due to its heavily iodinated composition, raising concerns about thyrotoxicity in patients with cardiovascular disease or other health conditions [14,15]. Thyroid dysfunction is reported in 15-20% of patients taking amiodarone [16]. While it is posited that AIM can cause hypothyroidism, many cases remain undiagnosed [17,18]. This systematic review aims to ascertain whether elderly patients receiving amiodarone are at increased risk of developing AIM.
This review is of paramount importance as myxedema coma is a severe, life-threatening condition resulting from untreated or poorly managed hypothyroidism. By understanding the relationship between amiodarone, a widely used medication, and the onset of myxedema coma, healthcare professionals can better recognize, prevent, and manage this critical condition. The review addresses the potential underdiagnosis of AIM, which is crucial for timely interventions to reduce morbidity and mortality. It further brings to light the necessity for vigilant monitoring and therapeutic modifications among the vulnerable population, especially elderly women, who are disproportionately affected. This analysis may also pave the way for the development of guidelines concerning amiodarone usage and thyroid function monitoring, ultimately contributing to improved patient care and outcomes. This review is guided by the Population, Issue of Interest, Comparison, Outcome, and Timeframe (PICOT) framework. The research question addressed here is: Are elderly patients administered amiodarone at risk of developing amiodarone-induced myxedema coma?
A preprint of this manuscript is available on Research Square [19].

Data Sources and Search Strategy
The authors followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to report this study. A systematic review of Medline (PubMed), Science Direct, CINAHL Cochrane database, and Google Scholar was performed to investigate the risk of developing myxedema coma in patients given amiodarone. Myxedema coma, amiodarone, induced, and side effects were all search terms used in this review. A limit on either English language and year of publication between 2016 and 2022 was imposed. All possible keyword combinations were searched, and a manual literature search was conducted.

Study Selection and Eligibility
The (PICOT) framework guided the inclusion criteria. The following case reports were considered for inclusion in the review: The population was elderly patients; the intervention is receiving amiodarone; the control is inapplicable for our study; and the outcome is myxedema coma caused by amiodarone. In addition, patients with mental illnesses were excluded. To ensure study eligibility, the authors independently screened the titles and abstracts returned by the searches. If there were any disagreements among researchers about the titles of any study, or the abstracts needed to provide more information, the full text (available and requested) was reviewed to determine if the paper met the inclusion criteria. The full texts (available and requested) of all publications that were determined to meet standards potentially were then examined to determine final inclusion. Any disagreements between reviewers were accepted through consensus or the addition of a third reviewer.

Data Extraction and Synthesis
This review was registered in the PROSPERO databases (CRD42023399719). All our findings are case reports only. Two reviewers reviewed each study, and disagreements about data abstraction were resolved through consensus or by a third reviewer. Based on data abstraction elements, data were summarized in numeric form.

Results
The study deletion process is shown in Figure 1. Our initial search yielded 1560 abstracts, of which 44 were found eligible based on initial screening and therefore underwent full-text review. Of the 44 case reports, 12 met the inclusion criteria and were included in the final evaluation. By analyzing the study characteristic, most patients were female (N=8, 66.7%), and most patients' age interval was 65-75 years old (41.6%). Also, the cases were reported in the USA, representing 75% of the case reports. Further, nine case reports (75%) of cases received care in the emergency department. Regarding the patient's condition, most cases had atrial fibrillation; see Table 1. 2023   The current reviews used the Joanna Briggs Institute (JBI) critical appraisal tool for the included case reports. This tool consists of eight questions that include four possible choices (Yes, No, Unclear, not applicable), and each question was concise and clearly defined. The critical appraisal result for the case report shows a good quality of research evidence. One study scored (100%) for all questions [12], and four case reports scored 87.5% [2,20,21]. Also, five case reports scored 75% [11,[22][23][24][25]. However, only one study scored 62.5% [26], as well only one study scored 50% [27]; see Table 2.  The abstracted data, including the study sample, setting, conclusion, and recommendation for all case reports, are presented in Table 3.   However, hypothermia and hypotension were reported about in half of the cases. Additionally, nine cases (75%) reported that the patients had no previous thyroid dysfunction [12,22,24,25,27,29,30], while three cases (25%) their patients had hypothyroidism [11,26,28]. Half of the included cases (50%) reported T3 and T4 levels [2,22,24,25,28,29], while the remaining did not [11,12,21,26,27,30].

Discussion
Myxedema coma is a syndrome caused by a severe thyroid hormone deficiency. Amiodarone is an iodinated derivative of benzofuran that can cause hypo-or hyperfunction of the thyroid. On the other hand, myxedema caused by amiodarone therapy is extremely rare [31]. In the current review, the precipitating factor that led to the development of myxedema coma was a history of amiodarone therapy [2,12,21,22,[28][29][30]. Amiodarone, which has a high iodine concentration, exerts its effects mostly through its structural relationship with thyroid hormones, and these two properties explain the changes in thyroid function reported. Amiodarone-induced thyrotoxicosis is more common in individuals who live in iodine-deficient areas and lead to several psychosocial impacts on adult patients [14,15,32,33]. While patients who consume enough iodine are more likely to develop hypothyroidism following amiodarone exposure, a condition known as AIM [34].
The incidence of AIM coma has been reported to range from 4% to 34% [35,36]. Female gender, older age, an underlying autoimmune thyroid disease, elevated baseline TSH levels, a starting dose of amiodarone greater than 200 mg/day, complex cyanotic heart disease, and residence in an iodine-sufficient region (e.g., the United States) are all risk factors for AIM [37][38][39]. Patients with myxedema coma in our review study were mostly female, older than 75 years, resided in an iodine-sufficient region (the United States), had atrial fibrillation, and started on amiodarone (200 mg/day).
The diagnosis of AIM depends on clinical manifestation (mental status, hypothermia, cold exposure, infection, drugs (diuretics, tranquilizers, sedatives, analgesics), trauma, stroke, heart failure, gastrointestinal bleeding), history or current amiodarone ingestion and the thyroid function tests [40,41]. Similarly, in the current review, most of the case reports showed the patients had elevated TSH, and 50% of the cases found that the patients had depressed T3 and T4 levels. Also, in three case reports in our review, the patients had a previous thyroid dysfunction (hypothyroidism). A mildly depressed thyroid panel with elevation in TSH was reported in the current review. It is critical to note that signs of thyroid dysfunction, as detected by thyroid panels, should be closely monitored in patients receiving chronic amiodarone therapy.
Patients with myxedema coma have common signs and symptoms such as hypothermia, bradycardia, hypotension, congestive heart failure, and hypoventilation with hypercapnia and respiratory acidosis [1,23]. Altered mental status, bradycardia, hypotension, and hypothermia are the most recurrent symptoms presented in our review for a patient diagnosed with myxedema coma who was on amiodarone, assessed by Glasgow Coma Scale and hemodynamic stability. The various possible causes of myxedema coma make diagnosis difficult. The symptoms of AIM are difficult to detect, especially in elderly patients with a history of heart disease who have further psychological symptoms in addition to inadequate adherence to their medication [15]. However, once diagnosed, often through clinical symptoms and serum TSH, this disease must be treated with thyroid hormone right away. Myxedema coma was successfully treated with levothyroxine and glucocorticoids, as presented in the included cases.
Myxedema coma is treated with hormone replacement therapy and supportive therapy. However, many countries still need to establish evidence-based treatment for myxedema coma because the disease is rare, and there is a lack of research in this area. Specific therapy entails giving levothyroxine [42,43], and most of the cases in the current review considered a maintenance dose of 100-200 g/day. Because absorption from the gut is unpredictable, the first dose should be administered intravenously, and this is consistent with all findings in this review that revealed levothyroxine was administered intravenously.
Myxedema treatment is associated with a risk of relative adrenal insufficiency; thus, glucocorticoid supplementation is needed [1,44]. In this review, five cases reported that glucocorticoid supplementation with hydrocortisone at 50-200 mg was administered intravenously. In addition, in this review, all cases reported that the patients received levothyroxine despite still taking amiodarone. This is supported by the current evidence suggesting that amiodarone can be continued in patients taking levothyroxine [41,45,46].
Moreover, it is critical to provide respiratory support through intubation, controlled mechanical ventilation, and supplemental oxygen therapy. Although the patient is hypothermic, external warming should be avoided because it can cause peripheral vasodilation and circulatory collapse. At room temperature, however, the patient can be covered with blankets [46].
A limitation of this systematic review, which primarily employs case reports to describe the relationship between amiodarone and the onset of myxedema coma, is the inherent weaknesses of case reports as a source of evidence. Case reports typically focus on an individual or a small number of cases and may not provide a comprehensive representation of the broader population. Additionally, they often lack control groups and blinding, making them susceptible to biases and confounding variables. The anecdotal nature of case reports means that causality cannot be definitively established, and the generalizability of findings is limited. Furthermore, the reliance on case reports may not sufficiently account for the diversity and complexity of clinical presentations and patient histories. It is important for future studies to employ more rigorous methodologies, such as randomized controlled trials or large-scale observational studies, to establish a more definitive and generalizable understanding of the association between amiodarone and myxedema coma.

Conclusions
In conclusion, diagnosing myxedema coma is an intricate process due to its diverse causes and often subtle symptoms, which is further complicated in elderly patients with a history of cardiac conditions. Early detection is critical and usually involves a combination of clinical assessments and TSH measurements. Once diagnosed, immediate initiation of thyroid hormone therapy, particularly a combination of levothyroxine and glucocorticoids, is essential. The case studies analyzed in this review suggest effectiveness in treating myxedema coma with this therapeutic approach. However, it is crucial to note that the evidence is drawn from a limited source -case reports, which lack the generalizability and rigor of larger-scale studies. This underscores the need for ongoing outpatient monitoring, particularly in assessing the long-term effects of AIM and monitoring patient recovery. Therefore, while the case studies provide valuable insights, further research employing more robust methodologies is necessary for a comprehensive understanding. Rapid identification and management of myxedema coma are vital to reducing the risk of life-threatening complications and improving patient outcomes. Through enhanced awareness and vigilant patient monitoring, especially in high-risk populations, the healthcare community can effectively address the challenges of myxedema coma and contribute to improved patient care.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.